Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis

Animesh Pardanani, Jason R. Gotlib, Catriona Jamieson, Jorge E. Cortes, Moshe Talpaz, Richard M. Stone, Michael H. Silverman, D. Gary Gilliland, Jolene Shorr, Ayalew Tefferi

Research output: Contribution to journalArticle

Abstract

Purpose: Myelofibrosis is a myeloid malignancy associated with anemia, splenomegaly, and constitutional symptoms. Patients frequently harbor JAK-STAT activating mutations that are sensitive to TG101348, a selective small-molecule Janus kinase 2 (JAK2) inhibitor. Patients and Methods: In a multicenter phase I trial, oral TG101348 was administered once a day to patients with high- or intermediate-risk primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Results: Fifty-nine patients were treated, including 28 in the dose-escalation phase. The maximum-tolerated dose was 680 mg/d, and dose-limiting toxicity was a reversible and asymptomatic increase in the serum amylase level. Forty-three patients (73%) continued treatment beyond six cycles; the median cumulative exposure to TG101348 was 380 days. Adverse events included nausea, vomiting, diarrhea, anemia, and thrombocytopenia; corresponding grades 3 to 4 incidence rates were 3%, 3%, 10%, 35%, and 24%. TG101348 treatment had modest effect on serum cytokine levels, but greater than half of the patients with early satiety, night sweats, fatigue, pruritus, and cough achieved rapid and durable improvement in these symptoms. By six and 12 cycles of treatment, 39% and 47% of patients, respectively, had achieved a spleen response per International Working Group criteria. The majority of patients with leukocytosis or thrombocytosis at baseline (n = 28 and n = 10, respectively) achieved normalization of blood counts after six (57% and 90%, respectively) and 12 (56% and 88%, respectively) cycles. A significant decrease in JAK2 V617F allele burden was observed at 6 months in mutation-positive patients (n = 51; P = .04), particularly in the subgroup with allele burden greater than 20% (n = 23; P < .01); the decrease was durable at 12 months. Conclusion: TG101348 is well tolerated and produces significant reduction in disease burden and durable clinical benefit in patients with myelofibrosis.

Original languageEnglish (US)
Pages (from-to)789-796
Number of pages8
JournalJournal of Clinical Oncology
Volume29
Issue number7
DOIs
StatePublished - Mar 1 2011
Externally publishedYes

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Janus Kinase 2
Primary Myelofibrosis
Safety
Anemia
Alleles
TG101348
Essential Thrombocythemia
Thrombocytosis
Polycythemia Vera
Mutation
Maximum Tolerated Dose
Sweat
Splenomegaly
Leukocytosis
Pruritus
Amylases
Serum
Cough
Thrombocytopenia
Nausea

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Pardanani, A., Gotlib, J. R., Jamieson, C., Cortes, J. E., Talpaz, M., Stone, R. M., ... Tefferi, A. (2011). Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. Journal of Clinical Oncology, 29(7), 789-796. https://doi.org/10.1200/JCO.2010.32.8021

Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. / Pardanani, Animesh; Gotlib, Jason R.; Jamieson, Catriona; Cortes, Jorge E.; Talpaz, Moshe; Stone, Richard M.; Silverman, Michael H.; Gilliland, D. Gary; Shorr, Jolene; Tefferi, Ayalew.

In: Journal of Clinical Oncology, Vol. 29, No. 7, 01.03.2011, p. 789-796.

Research output: Contribution to journalArticle

Pardanani, A, Gotlib, JR, Jamieson, C, Cortes, JE, Talpaz, M, Stone, RM, Silverman, MH, Gilliland, DG, Shorr, J & Tefferi, A 2011, 'Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis', Journal of Clinical Oncology, vol. 29, no. 7, pp. 789-796. https://doi.org/10.1200/JCO.2010.32.8021
Pardanani, Animesh ; Gotlib, Jason R. ; Jamieson, Catriona ; Cortes, Jorge E. ; Talpaz, Moshe ; Stone, Richard M. ; Silverman, Michael H. ; Gilliland, D. Gary ; Shorr, Jolene ; Tefferi, Ayalew. / Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. In: Journal of Clinical Oncology. 2011 ; Vol. 29, No. 7. pp. 789-796.
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AU - Pardanani, Animesh

AU - Gotlib, Jason R.

AU - Jamieson, Catriona

AU - Cortes, Jorge E.

AU - Talpaz, Moshe

AU - Stone, Richard M.

AU - Silverman, Michael H.

AU - Gilliland, D. Gary

AU - Shorr, Jolene

AU - Tefferi, Ayalew

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N2 - Purpose: Myelofibrosis is a myeloid malignancy associated with anemia, splenomegaly, and constitutional symptoms. Patients frequently harbor JAK-STAT activating mutations that are sensitive to TG101348, a selective small-molecule Janus kinase 2 (JAK2) inhibitor. Patients and Methods: In a multicenter phase I trial, oral TG101348 was administered once a day to patients with high- or intermediate-risk primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Results: Fifty-nine patients were treated, including 28 in the dose-escalation phase. The maximum-tolerated dose was 680 mg/d, and dose-limiting toxicity was a reversible and asymptomatic increase in the serum amylase level. Forty-three patients (73%) continued treatment beyond six cycles; the median cumulative exposure to TG101348 was 380 days. Adverse events included nausea, vomiting, diarrhea, anemia, and thrombocytopenia; corresponding grades 3 to 4 incidence rates were 3%, 3%, 10%, 35%, and 24%. TG101348 treatment had modest effect on serum cytokine levels, but greater than half of the patients with early satiety, night sweats, fatigue, pruritus, and cough achieved rapid and durable improvement in these symptoms. By six and 12 cycles of treatment, 39% and 47% of patients, respectively, had achieved a spleen response per International Working Group criteria. The majority of patients with leukocytosis or thrombocytosis at baseline (n = 28 and n = 10, respectively) achieved normalization of blood counts after six (57% and 90%, respectively) and 12 (56% and 88%, respectively) cycles. A significant decrease in JAK2 V617F allele burden was observed at 6 months in mutation-positive patients (n = 51; P = .04), particularly in the subgroup with allele burden greater than 20% (n = 23; P < .01); the decrease was durable at 12 months. Conclusion: TG101348 is well tolerated and produces significant reduction in disease burden and durable clinical benefit in patients with myelofibrosis.

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